Thymic Tolerance in Pediatric Heart Transplantation

目前，儿童心脏移植的主要限制包括与传统非特异性免疫抑制相关的副作用、高成本和侵入性排斥反应监测以及目前免疫抑制剂无法预防慢性排斥反应（移植后冠状动脉病变）。如果能够实现供体特异性“移植耐受”（移植医学的圣杯），这些限制可能会被消除。供体特异性耐受可以定义为受者免疫系统对供体抗原无反应，无需长期抗排斥治疗即可永久接受同种异体移植物，但对非供体抗原仍保持正常免疫反应的状态。感染的风险，淋巴增生性疾病，

Major limitations in pediatric heart transplantation at this time include the side effects associated with conventional non-specific immunosuppression, the high costs and invasive nature of rejection surveillance and the inability to prevent chronic rejection (post-transplant coronary vasculopathy) with our current armamentarium of immunosuppressive agents. These limitations might be eliminated if donor-specific 'transplantation tolerance' (the Holy Grail of transplantation medicine) could be achieved. Donor-specific tolerance can be defined as a state in which the recipient's immune system is non-reactive to donor antigens and will permanently accept the allograft without the need for long-term anti-rejection therapy, yet retains normal immune responses to non-donor antigens. The risks of infection, lymphoproliferative disorders, malignancy and end-organ drug toxicities are thus avoided. Tremendous efforts have been expended over the last 50 years to understand how transplantation tolerance can be achieved and experiments in small animals have now been extended to subhuman primates. However, few studies have moved to the clinical arena, and none have been performed in pediatric thoracic transplantation. Since pediatric transplantation offers little chance of long-term survival into mid-adult life, we believe that it is time for the most promising laboratory techniques for tolerance induction to be cautiously extended to the clinic. Rationale for the 'thymic' approach to tolerance induction in pediatric heart transplantation comes from several avenues: i). the importance of the thymus gland for T cell maturation in early childhood; ii). a growing experimental literature showing successful induction of donor-specific tolerance by inoculation of the recipient thymus with donor-specific antigens; and iii). the excellent exposure of the thymus obtained during median sternotomy at time of heart transplantation. A pilot study at our institution provides preliminary data to suggest that this approach is feasible, safe and potentially effective. We therefore propose a prospective, blinded, controlled clinical trial of inoculation of unmodified donor-specific bone marrow cells into both lobes of the recipient thymus gland at the time of heart transplantation. We hypothesize that the induction of thymic tolerance will be safe and will reduce acute rejection events and long-term requirements for immunosuppressive medications when compared to contemporary controls that do not receive donor-specific intra-thymic bone marrow inoculation. We also hypothesize that the improved outcomes will be associated with in vitro evidence of donor-specific hyporesponsiveness.